The objective of this program project is to identify genetic, CNS, and environmental sources of variability that explain the variations in neurobehavioral outcomes associated with spina bifida meningomyelocele (SB), the most common severely disabling birth defect in North America. In the previous five years, the investigative team identified several potential candidate genes that were associated with clinical markers (e.g., lesion level) and ethnicity. These clinical markers accounted for genetic and neurological variability and were linked to outcomes. They identified processes that cross domains of cognitive and motor function (e.g., timing) and related them to brain dysmorphology. In this continuation application, the investigators propose to evaluate 450 children and adults with SB, 20 with aqueductal stenosis, and 277 controls in four projects and three cores at two primary data collection sites: the University of Texas-Houston, and The Hospital for Sick Children, Toronto. Project I (Genetics;Northrup, PI) evaluates genetic factors associated with SB and related neural tube defects in a sample of over 2,000 Hispanic and Caucasian participants. Different statistical models will be used to test candidate genes for genetic linkage/associations and to evaluate environmental factors related to the heritability of SB. Project II (Early Learning;Landry, PI) continues a longitudinal study of 85 infants with SB and 73 controls identified at birth, following them to 7.5, 8.5, and 9.5 years of age. This study addresses the early development of core neurocognitive deficits in SB in relation to environmental factors (SES, parenting) that produce school age outcomes. Project III (Neurocognitive;Dennis, PI) evaluates core neurocognitive processes in relation to brain dysmorphology in children and adults with SB, extending the study across the life span. Project IV (Magnetic Source Imaging;Papanicolaou, PI) utilizes magnetic source imaging to evaluate the reorganization of motor, somatosensory, language, and cognitive skills in children with SB and AS, representing one of the first functional neuroimaging studies of children with congenital brain injury. These four projects are supported by an Administrative Services Core (A;Fletcher, PI), Subject Recruitment and Evaluation Core (B;Fletcher, PI), and Database and Statistics Core (C;Francis, P.I.). This comprehensive program project will facilitate an integrated, multidisciplinary understanding of SB and provides a model for other neurodevelopmental disorders with genetic heterogeneity, brain dysmorphologies, and variable neurobehavioral outcomes.